Nitrofuran derivatives of pseudoureas



United States Patent 3,549,625 NITROFURAN DERIVATIVES 0F PSEUDOUREASHermann Breuer, Regensburg, Germany, assignor to E. R. Squibb & Sons,Inc., New York, N.Y., a corporation of Delaware No Drawing. Filed Dec.5, 1967, Ser. No. 687,980 Claims priority, application Germany, Dec. 9,1966,

Int. oi. C07d /46 US. Cl. 260-240 15 Claims ABSTRACT OF THE DISCLOSUREThis invention relates to antimicrobially active nitrofuran derivativesof pseudoureas having the general forrnula SUMMARY OF THE INVENTION Thisinvention relates to nitrofuran derivatives of pseudoureas having theformula This formula may also be written in the tautomeric form FormulaI will be used herein as representative of both tautomeric forms.

R in the formula represents a straight or branched chain lower alkylgroup such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,t-butyl, amyl or the like. It also represents a lower alkoXy-loweralkylene or lower alkylthio-lower alkylene group in which the alkylchains may be straight or branched, e.g., methoxymethylene,methoxyethylene, ethoxymethylene, ethoxyethylene, methylthiomethylene,ethylthiomethylene and the like. R also represents a cycloalkyl group of3 to 8 carbon atoms, e.g. cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and cyclooctyl, as well as aralkyl groups, preferablyphenyl-lower alkyl groups such as benzyl, phenethyl and the like.

R may represent hydrogen, but preferably it represents an acyl group,especially a lower alkanoyl group such as acetyl, propionyl, butyryl orthe like, or benzoyl, monosubstituted benzoyl, e.g., halobenzoyl,nitrobenzoyl, lower alkyl-benzoyl and the like. In a more preferred formthe acyl group is a nitrofuroyl or a nitrofuranacryloyl group so thatthere is obtained a bis compound of the formula (III) R In all of theforegoing formulas X represents oxygen, which gives the pseudoureaseries of compounds, or sulfur, which gives the thiopseudourea seriesand n is 0 or 1.

The foregoing compounds of this invention are useful as antimicrobialagents, e.g., in combatting organisms such as Trichomonas vaginalis,Trichomonas foetus, Staphylococcus aureus, Salmonella schoztmuelleri,Pseudomonas aeruginosa, Proteus vulgaris, Escherischia coli,Trychophyton mentagrophytes, as well as other species of such genera orthe like. For example, they may be administered orally to various animalspecies, e.g., mice in an amount of about 5 to 25 mg./kg./ day,preferably in 2 to 4 divided doses, in any of the conventional oraldosage forms, or topically in creams in equivalent amounts. They may beused as surface disinfectants. About 0.01 to 1.0% by weight of any ofthese substances may be dispersed on an inert solid or in a liquid suchas water and applied as a dust or spray or incorporated in a soap orother cleansing agent such as a solid or liquid detergent composition.The latter may be used, for example, in general cleaning, in cleaningdairy barns or dairy, food handling or food processing equipment.

The compounds of this invention may be prepared by several methods asdescribed hereinafter. The symbols have the meaning described above.According to one method, a pseudourea derivative of the formula (IV) R1or its salt with an inorganic acid is treated with a S-nitro- 2-furoylor S-nitro-Z-furanacryloyl compound to first introduce a5-nitro-2-furoyl group or a S-nitro-Z-furanacryloyl group. Then, ifdesired, a second acyl group may be introduced into the molecule. Inorder to obtain the N,N- diacylated compounds of this invention, theintroduction of the acyl groups may also be effected in the reverseorder. If the same acyl group is introduced on each nitrogen atom, thereaction may be carried out so as to add both acyl groups in a singlestep (e.g. by adjusting the proportions of reactants). The followingflow schemes are illustrative of the alternate routes:

An alternative method for preparing compounds of this inventioncomprises converting an acylcyanamid with an alcohol or mercaptan to themonoacyl pseudothiourea derivative, if desired, introducing another acylgroup according to the following reaction scheme.

(VII) Finally, compounds of this invention may be prepared by nitratinga furan substituted pseudourea or pseudothiourea as follows:

The following examples are illustrative of the invention.

EXAMPLE 1 (a) 13 grams of O-methyl pseudourea sulfate are dissolved in150 ml. of pyridine and a solution of 18 gms. of S-nitrofuranacrylicacid chloride in 120 ml. of dry chloroform is added dropwise. This isstirred for four hours at room temperature, the solvent is distilled offunder vacuum, the residue is washed with water and sodium bicarbonateand filtered under suction. The yield amounts to 80% of theory. The2-methyl-l-(5-nitro-2- furanacryloyl)psendourea is recrystallized fromdioxane, M.P. 238-240" C. with dec.

(b) The product of part (a) is acylated by adding to a solution of2-methy1-1-(5-nitro-2-furanacryloyl)pseudourea in pyridine a solution ofacetyl chloride in dry chloroform to obtain3-acetyl-2methyl-1-(S-nitro-Z-furanacryloyl) pseudourea.

N O2-L 4 EXAMPLE 2 To a suspension of 14 grams of S-methyl pseudoureasulfate in 150 ml. of dry pyridine is added dropwise a solution of 26gms. of 5-nitro-2furanacrylic acid chloride in 250 ml. of dry chloroformwith slight cooling. After the addition of the acid chloride aprecipitate forms. This is stirred for three hours at room temperatureand then the solvent is evaporated under vacuum.

The residue is washed with water and sodium bicarbonate, then filteredunder suction. The product is recrystallized from dioxane. The yieldamounts to 70% of theory.

The product, 2-methyl-l,3-bis[S-nitro-Z-furanacryloyl]- Z-thiopseudoureahas a melting point of 210 C., with dec.

EXAMPLE 3 10 grams of N,N'-di(S-nitro-Z-furoyl)carbodiimidepyridinecomplex are suspended in 50 ml. of pyridine and the suepension, afterthe addition of 20 ml. of ethanol with stirring, is heated for about 30minutes until a clear solution results. The solution is evaporated todryness, the residue is taken up in a little ethanol and the crystalsare filtered under suction. 3.6 gms. of 2-ethyl- 1,3-bis[5-nitro 2furoyl)pseudourea are obtained. The

product is recrystallized from dioxane and melts at 201- 202 C.

EXAMPLE 4 100 ml. of ethylene glycol monomethyl ether are heated to 80.10 gms. of N,N-di(5-nitro-2-furoyl)carbodiimide are added with stirringand the mixture is cooled to room temperature as soon as a clearsolution is obtained. The crystals which precipitate upon the additionof water are filtered under suction and recrystallized from ethyleneglycol monomethyl ether.

The yield amounts to 3.7 gms. of 2-(2-methoxyethyl)-1,3-bis(5nitro-2-furoyl)pseudourea, M.P. 14014l C.

EXAMPLE 5 Additional compounds having the following formula and thesubstituents indicated in the table may be produced by the procedure ofthe example also indicated 5 in the table, substituting theappropriately substituted Procedure of Example R1 CzHsS Calf;

EXAMPLE 6 Additional compounds having the following formula and thesubstituents indicated in the table may be produced by the procedure ofthe example also indicated in the table, substituting the appropriatelysubstituted realkanoyl, 'benzoyl, halobenzoyl, nitrobenzoyl, loweralkylactant: benzoyl, nitrofuroyl or nitrofuranacryloyl, X is oxygen orsulfur and n is or 1.

2. A compound of the formula 1 i l N02 0 (OH=CH),,G0NH-C=N-0O-(CH=0H),,O NO R1 wherein R X and n have the same meaning as in claim 1. Q 3. Acompound as in claim 1 wherein R is lower alkyl,

R is hydrogen, X is oxygen and n is 0.

| O NHC=N R2 4. A compound as in claim 1 wherein R is lower alkyl,

R is hydrogen, X is oxygen and n is 1.

Procedure of 5. A compound as in claim 1 wherein R is lower alkyl,

Example R1 R2 X 11 R is hydrogen, X is sulfur and n is 1.

1 ,3 H 0 0 6. A compound as in claim 2 wherein R is lower i g g alkyl, Xis oxygen and n is 0. 1 C2H SOgH CHaCO s 1 7. A compound as in claim 2wherein R is lower alkyl, %ggg;1 gislgoo g 1:20 xgssiilfurandnhsoi l' 2h R 'l lkl a 4 compoun as 1n c aim w erein 1 1s owera y 32 32 0 g l X isoxygen and n is 1. 1 3 2 Z Z S 1 A compound as 1n claim 2 wherein R; islower alkyl,

XIS sulfurandnis l. h 1 10. A compound as in claim 2 wherein R is lowerX 2 15 c almeg h f 1 alkoxy-lower alkylene, X is oxygen and n is 0.

' Compoun o t G 0mm a 11. A compound as in claim 2 wherein R is loweralkoxy-lower alkylene, X is oxygen and n is l. 12. A compound as inclaim 4 wherein the lower alkyl X group is methyl. N20 -(o11 cH 13. Acompound as in claim 6 wherein the lower alkyl group is ethyl.

14. A compound as in claim 9 wherein the lower alkyl wherein R is loweralkyl, lower alkoxy-lower alkylene, g p is methyllower alkylthio-loweralkylene, cycloalky of 3 to 8 car- 15. A compound as in claim 10 whereinthe lower bon atoms or phenyl-lower alkyl, R is hydrogen, loweralkoxy-lower alkylene group is methoxyethylene.

References Cited UNITED STATES PATENTS 2,779,669 1/ 1957 Snyder 71-2.6

HENRY R. JILES, Primary Examiner G. T. TODD, Assistant Examiner US. Cl.X.R. 260-3472, 347.3; 424-285 mg UNITED STATES PATENT OFFICE CERTIFICATEOF CORRECTION Patent No. 5 Dated December 22, 1970 Invent Hermann BreuerIt is certified that error appears in the above-identified patent andthat said Letters Patent are hereby corrected as shown below:

I The formula in Claim 1 should read as follows:

{I ll NO- --(CH=CH) n The formula in Claim 2 should read as follows:

(CH=CH) LLNO Signed and sealed this 25th day of May 1971.

' (SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, Attesting OfficerCommissioner of Paten

